3-substituted aminoethoxyandrosta-3, 5-dienes



United States Patent This invention relates to new steroid compounds.More particularly, it relates to 3-substituted androsta-3.,5-dienes andmethods of preparing the same.

The novel steroids 0f the present invention can be illustrated by thefollowing structural formula:

in which R is hydrogen or lower alkanoy-l; R and R" are lower alkyl; and

is a heterocyclic radical containing (1) carbon and nitrogen atoms or(2) carbon, nitrogen and oxygen atoms; X is hydrogen or a halogen atom;C is a: radical of the group and n is an integer from 2 to 4.

The present compounds are prepared by using as starting materials,steroids described in the prior art such as testosterone acetate,

N 2) nO 17,8 propionyloxy-9u-chl0ro-11fi-hydroxyandrost-4-en-3-- one,l7fi-acetoxy-9a-bromo 11B hydroxyandrost-4-en-3-one and the like. Thesestarting materials are reacted with a trilo wer alkylorthoformatepreferably in the presence of a solvent such as, for example, d-ioxane,or an absolute alcohol and in the presence of a strong acid such asperchloric acid. The corresponding lower alkyl enolether of theandrost-4-ene-3-one is obtained in each instance.

The steroid intermediates prepared immediately above are reacted with analkylene chlorohydrin such as ethylenechlorohydrin,propylenechlorohydrin or butylenechlorohydrin to produce thecorresponding 3 (fl-chloroethoxy)- 3,5-androst adiene,3('yachloropropoxy)-3,S-androstadiene and3(E-chlorobutoxy)-3,5-androstadiene, respectively. The reaction takesplace readily at room temperature. The resulting product is generallycrystalline and can be recovered and purified by methods Well known tothose skilled in the art.

The w-chloroalkyleneoxy-3,S-androstadiens described above are reactedwith secondary amines which replaces the chloro group with thecorresponding amine group. Among the amines found useful in the processof the present invention are, for example, dimethylamine, diethylamine,dipropylamine, diisopropylamine, dibutylamine, diisob-utylamine,methylethylamine, methylpropylamine, methylbutylamine, ethylpropylamine,ethylbutylamine, propylbutylamine, pyrrolidine, dibenzylamine,piperidine, morpholine, hexamethyleneimine and the like. The productsresulting from the reaction which are the novel products of the presentinvention are illustrated in the examples hereinafter. The process iscarried out preferably in a solvent such as acetone, when the amineboils at a temperature below C., by heating the reactants in a closedvessel for from 5 to 24 hours. When the amines boil at temperaturesabove 85 C., an excess of the amine acts as a solvent as well asreactant. The purified amino products can be obtained by the usualmethod of purification.

The process to prepare the compounds of the present invention can beillustrated by the following flowsheet.

CH3 C 3 OR OR CH3/\ I CH: l

Cu Cn I X i l X I II l nC1 CH3 CH3 OR OR CHa/\ CH3 1 Cl(CH2)nO IV 3wherein R is hydrogen or lower alkanoyl; R and R" are lower alkyl; and

/N BI! is a heterocyclic radical containing (1) carbon and nitrogenatoms or (2) carbon, nitrogen and oxygen atoms; X is hydrogen or ahalogen atom; C is a radical of the group I I (5)011 CH2, 0/ l I.

and n is an integer from 2 to 4.

The compounds of the present invention have been found to haveanti-cholesteremic activity. This activity in rats is indicative ofusefulness in the treatment of hypercholesteremia.

The following examples illustrate the preparation of representative3-substituted androsta-3,5-dienes of the invention.

Example 1.--Preparati0n of 17 3-11Cet0xy-3-Metlz0xy3,5- AndrostadieneTestosterone acetate, 10.0 g., is suspended in a solution of 50 m1. ofdioxane, 5.0 ml. of trimethylorthoformate and 0.5 ml. of absolutemethanol. Four drops of 72% perchloric acid are added to the reactionmixture. After five minutes 1.0 ml. of pyridine is added and thesolution with suspended pyridinium salt is poured into water andfiltered giving 10.35 g. of the enol ether, melting point 160-165 C.Crystallization of a portion of this material from methanol in which itis considerably soluble raises the melting point to l76180 C.

Following the procedure described above and substituting the followingcompounds in place of testosterone aoetate, in each instance the desiredenol ether is obtained.

17B-acetoxyandrost-4-ene-3,l l-dione 17B-acetoxy-11B-hydroxyandrost-4-en-3-one 17,3-acetoxy-9afluoroandrost-4-ene-3,1l-dione 17 B-ZCCIOXY-Qoc-flllOlO-l l p-hydroxyandrostl-en-3-one.

Example 2.-Preparati0n of 17fi-Acetoxy-3Q3-Clzlor0- ethoxy-3,5-Androsmdiene To l7B-acetoxy-3-methoxy-3,5-androstadiene (1.0 g.) isadded commercial ethylenechlorohydrin (10 ml.) and after standing 5minutes at room temperature the now dark homogenous solution is treatedwith pyridine (4 drops) and diluted with methylene chloride (50 ml.).This solution is pased through a short column of a synthetic magnesiumsilicate followed by an additional amount of methylene chloride (200ml.). The effluent is evaporated to dryness to give a. crystallineresidue which is crystallized from methanol to give the fl-chloroethoxyenol ether, melting point 130-l32 C.

Following the procedure of the above example and substituting thefollowing compounds in place of 17fi-acetoxy3-methoxyandrosta-3,S-diene, in each instance, the desired fl-chloroenol ether is obtained.

17B-acetoxy-3-methoxyandrosta-3,S-dien-l l-one17/S-acetoxy-11fl-hydroxy-3-methoxyandrosta-3,S-diene17fl-acetoxy-9a-fluoro-3 -methoxyandrosta-3,5-diene-1 1- one17fi-acetoxy-9u-fluoro-1 1l9-hydroxy-3-methoxyandrosta-3,

S-diene.

Example 3 .Preparation of I 7,3-Acetoxy-3 (pl-Secondaryaminoethoxy-Andr0sta-3,5-Dienes A sample of 17,8-acetoxy-3(fi-chloroethoxy)-androsta- 3,5-diene (0.5 g.) is dissolved in acetone(25 ml.) and one equivalent of sodium iodide is added. To the abovemixture in a pressure flask is'added a secondary amine (at leastequivalent but normally more than five) and this is heated at 85 C. for24 hours. The reaction mixt re is then filtered, evaporated to drynessand dissolved in methylene chloride. Passage of this solution through ashort magnesium silicate column and subsequent evaporation of thesolvent gives the desired p-aminoethoxy compounds.

For amines boiling above 85, the use of the pressure flask and acetonesolvent is not required since the chloroethoxy compound is refluxed withthe desired amine to give the corresponding fl-aminoethoxy compound.

In the manner of the above example and substituting the followingcompounds in place of l-acetoxy-3(5- chloroethoxy)-androsta-3,5-diene,in each instance, the fl-aminoethoxy compound is obtained.

17fl-acetoxy-3 (,B-chloroethoxy) -androsta-3 ,5 -dien-1 l-onel7fl-acetoxy-3 fi-chloroethoxy) 1 l-hydroxyandrosta-3 ,5

diene 17 3-acetoxy-3 (B-chloroethoxy) -9a-fluoroandrosta-3,5-

dien-l l-one 17l3-acetoxy-3 (fl-chloroethoxy)-9u-fluoro-1lfl-hydroxyandrosta-3,5-diene.

Following the procedure described in the present example and using theamines: dimethylamine, diethylamine, dipropylamine, diisopropylamine,dibutylamine, diisobutylamine; pyrrolidine, dibenzylamine, piperidine,morpholine the following compounds are obtained.

17,8-acetoxy-3 fi-dimethylaminoethoxy) -androsta-3 ,5

diene;

l7fi-acetoxy-3 (B-diethylaminoethoxy -androsta-3 ,5 -diene;

17fi-acetoxy-3 (fl-diisopropylaminoethoxy) -androsta-3 ,5

diene;

17 fi-acetoxy-3 (,B-dipropylaminoethoxy -androsta-3 ,5-

diene;

l7fl-acetoxy-3 (fl-dibutylaminoethoxy -androsta-3 ,5 -dicnc;

l7fl-acetoxy-3 fi-diisobutylaminoethoxy -androsta-3 ,5

diene;

17,8-acetoxy-3 (fi-pyrrolidinoethoxy) -androsta-3 ,5 -diene;

17 3-acetoxy-3 (fl-dibenzylaminoethoxy) -androsta-3 ,5-

diene;

17/.3-acetoxy-3 (fl-piperidinoethoxy) -androsta-3 ,5 -diene;

17/3-acetoxy-3 (fl-morpholinoethoxy) -androsta-3 ,5 -diene;

l7fl-acetoxy-3 fl-dimethylaminoethoxy -9 a-fillOrO-llflhydroxyandrosta-3 ,5 -diene;

17/3-acetoxy-3 (fi-diethylaminoethoxy)-9a-fluoro-1lfi-hydroxyandrosta-S,5 -diene;

17B-acetoXy-3 fl-diisopropylaminoethoxy) -9 a-fluoro-l 1,8-

hydroxyandrosta-3 ,5 -diene 17fi-acetoxy-3 (fl-dipropylaminoethoxy-9m-fluoro-l 1,9-

hydroxyandrosta-3 ,5 -diene;

17/3-acetoxy-3 (fi-dibutylaminoethoxy) -9 a-fluoro-l 1fi-hydroxyandrosta-3 ,5 -diene;

17 8-acetoxy-3 B-diisobutylaminoethoxy -9 u-fluoro-l 113-hydroxyandrosta-3 ,S-diene;

17fl-acetoxy-3 fi-pyrrolidinoethoxy) -9 a-fluoro-l lfl-hydroxyandrosta-3,S-diene;

l7fi-acetoxy-3 (B-dibenzylaminoethoxy) -9 a-fluoro-l lfl-hydroxyandrosta-3 ,5 -diene;

17/3-acetoxy-3 fi-piperidinoethoxy -9 a-fluoro-l lfi-hydroxyandrosta-3,S-diene;

17fl-acetoxy-3 (fi-dimethylaminoethoxy) -1 LB-hydroxyandrosta-3 ,5-diene;

17 fi-acetoxy-3 B-diethylaminoethoxy -l 1 fl-hydroxyandrosta-3 ,5-diene;

17B-acetoxy-3 (B-diisopropylaminoethoxy) -l l fi-hydroxyandrosta-3 ,5-diene 17B-acetoxy-3 B-dipropylaminoethoxy) -l lfl-hydroxyandrosta-3 ,5-diene;

17 B-acetoxy-B fl-dibutylaminoethoxy) -1 1 fl-hydroxyandrosta-3 ,5-diene;

17/3-acetoxy-3 (B-diisobutylaminoethoxy) -1 lB-hydroxyandrosta-3,S-diene;

17fl-acetoxy-3 fl-pyrrolidinoethoxy) -l l p-hydroxyandrosta-3 ,5 -diene;

1. A COMPOUND OF THE FORMULA: